This is a second revision to a competing renewal for 5 years of funding to extend a research program entitled "MRI/MRSI Studies of Bipolar Treatment Response." The original application was funded for a 3-year period and the project was conducted both at Harvard/McLean Hospital and the University of Washington. Major findings during the prior period of funding include (1) observation of a diffuse pattern of neurochemical change consistent with mitochondrial dysfunction (increased gray matter lactate and glutamate/glutamine/GABA (Glx)) in untreated patients with bipolar disorder;(2) measured changes toward normal values in brain Glx were associated with lithium treatment, but not valproic acid therapy;and (3) neuroanatomic alterations identified using voxel based morphometry and shape analyses were associated with a bipolar disorder diagnosis. This revised application is focused on the role that mitochondrial dysfunction plays in bipolar disorder. In addition to our prior MRSI findings, recent, independent, post-mortem data suggests that "pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation" is present in brain tissue from individuals with bipolar disorder (Konradi et al., 2004). To support the hypothesis that these energetic abnormalities may create a novel therapeutic target for the treatment of bipolar disorder, extensive new preliminary data on the effects of cytidine on mood and brain chemistry is provided. Clinically, cytidine was more effective than placebo in improving the symptoms of bipolar depression when added to divalproex. Intriguingly, in contrast to the effects of lithium, cytidine appears to reduce both Glx and brain lactate levels. All studies proposed in this revised application will be performed at the McLean Hospital Brain Imaging Center. Studying in total of 130 subjects with bipolar disorder and 60 healthy comparison subjects, 3 specific lines of research will be pursued. Specific projects are designed to (1) further characterize changes in brain chemistry related to altered mitochondrial function in bipolar disorder using multinuclear (phosphorus-31 and hydrogen-1) magnetic resonance spectroscopic imaging at high-field;(2) evaluate the therapeutic efficacy and the neurochemical effects of uridine, a neurochemical to which cytidine is converted in man, compared to paroxetine in lithium treated bipolar subjects;and (3) utilize novel morphometric methods to better understand neuroanatomic correlates of disease manifestation and treatment effects.